[CONTRIBUTION FROM THE CHEMISTRY DEPARTMEKT OF THB UXIVERSITY OR K ~ T U C K Y ]
SULFONAL ANALOGS DERIVED FROM TETRAHYDROTHIAPYRAN CHARLES BARKENBUS
AND
VALVA C. MIDRIFF
Received January 8 , 1961
No mercaptols or their corresponding sulfones of tetrahydro-1 ,4-thiapyrone have been made. The close structural relationship between the sulfonal type of hypnotic (I) and these sulfones (11) can be seen from their formulas.
CH, CH2
\ / C / \
CHa CH2
SOz CzH6
/CHz CH2\
02s SO, CzHs
\
CH2 CH2
802 CzHs
/ C / \
SO2 CBHS
I1
I
The sulfonal type of structure reaches its maximum hypnotic activity when all four of the alkyl groups are ethyl groups. In this series of sulfones two of the ethyl groups are attached to a tetrahydro-l,4-thiapyran-l-dioxidestructure thus increasing the sulfone groups to three. Due to the possibility that sulfones of this structure might have some interesting physiological properties several sulfones of this type have been synthesized. It was found, however, that they had no hypnotic activity on rats which was probably due to their marked insolubility in appropriate so1vents.l The ethylmercaptols were easily made in excellent yields from all of the tetrahydro-l,4-thiapyrones used. The very stable beta-keto ester, 2,6-dimethyI3-carbomethoxytetrahydro-l .4-thiapyrone, which is very resistant to hydrolysis (l), formed an ethylmercaptol readily. It was also found possible to prepare the ethylmercaptol of tetrahydro-1 ,4-thiapyrone-l-dioxide which was a very viscous liquid that distilled under diminished pressure but never solidified. The rnercaptol of 3-ketothiophane was also made. The mercaptols Kere clear colorless stable liquids which could be purified by distillation under diminished pressure. The mercaptols made are listed in Table I. The corresponding sulfones were made by oxidizing the mercaptols with potassium permanganate using essentially the procedure of Reitz ( 2 ) .They are white crystalline solids fairly soluble in chloroform and hot acetone but practically insoluble in cold water. It was possible to prepare a sulfone from all the mercaptols made. They are listed in Table 11. EXPERIMEKTAL
Preparation of 4,Q-bis(ethylmercopto)tetrah~drothiapyran.I n a smell flask were placed 11.6 g. (0.1 mole) of tetrahydro-1,4-thiapyroneand 14.9 g . (0.24 mole) of ethylmercaptan. The mixture was cooled with ice and anhydrous hydrochloric acid was slowly passed into 1 W e are indebted t o Dr. R1[. 6. Van Campen of the Wm. S. Rferrell Coinpany for evaluating the hypnotic activity of these sulfones. 1047
1048
CHARLES BARHENBUS AX'D VALVA C. MIDKIFF
the mixture for three hours. After standing a t 0" overnight, ether and water were added and the ether layer separated. The ether solution was washed well with cold 6% sodium hydroxide, then with ice-water, and dried over magnesium sulfate. After distilling off t h e
s? B.P.,
MERCAPTOL
4'
"c./MU.
SULBUP FOaMULA
Calc'd Found --
4,4 - bis(Ethy1mercapto)tetrahydrot'hiapyran . . . . . . . . . . . . . . . . . . . . . . . . . 86 3 - Methyl - 4,4 - bis(ethy1mercapto)tetrahydrothiapyran. . . . . . . . . . . . . . . 77 2 - Methyl - 4 , 4 - bis(ethy1mercapto)tetrahydrothiapyran. . . . . . . . . . . . . . . 95 2,6 Dimethyl - 4 , 4 bis(ethy1mercapt,o)tetrahydrot,hiapyran... . . . . . . 63 2,6 -Dimethyl - 3 - carbomethoxy -4,4bis (ethylmercapto) tetrahydrothiapyran. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 4,4 - bis (Ethy1mercapto)tetrahydrothiapyran 1 - dioxide., , . , . , , , , 56 3 , 3 - bis (Ethy1mercapto)thiophane. 63
-
-
-
a
112-114/2
1.5635' CoHlsSs
114-116/2
1.5625
CIOHZOS~40.68 41.10
112-114/2
1.5552
CloH&31
40.68 40.98
€08-110/1.5
1.5418
CllHzzSa
38.41 38.24
CisH2a02S3 31.18 30.93
144-14612.5" 172-175/2 112-114/2.5
43.25 43.40
1. ,5505 1.5669
COHISOZS~37.81 37.96 CsHleSs 46.16 45.91
M.P. 5062". TABLE II 4, 4-BIB (ETHYLSULFONYL)TETRAHYDROTHIAPYRAN-1-DIOXIDES 3, ~-BIS(ETHYLSULFONY THIOPHANEDIOXIDE
AND
YIELD,
SULFONES
%
I
- -
F O ~ L A
-Calc'd
Found
1m.5-171.5
30.21
30.48
183-166
28.94
29.34
46.3
165-167
28.94
29.16
57.8
199.5-200.5
27.76
27.63
45.8
169 -170
23.78
23.05
51.4
192.6-193.5
31.60
31.55
- Methyl - 4,4 - bis(ethylsulfony1)-
tetrahydrothiapyran - 1 dioxide.. . 2,6 - Dimethyl - 4,4 - bis(ethylsu1fong1)tetrahydrothiapyran - 1 - dioxide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,6 - Dimethyl - 3 - carbomethoxy4,4 - bis(ethylsulfony1)tetrahydrothiapyran 1 dioxide.. . . . . . . . . . . . 3,3 - bis(Ethylsulfony1)thiophanedioxide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
"C.
____ 4,4 - bis(Ethylsu1fonyl)tetrahydrothiapyran - 1 - dioxide.. . . . . . . . . . . . . . . 60.0 3 - Methyl - 4,4 - bis(ethylsu1fonyl) tetrahydrothiapyran - 1 - dioxide.. , 53.5 2
SULFG3
Y.P.,
__
solvent t h e mercaptol was fractionally distilled under diminished pressure. The other mercaptols were made in a similar manner and the yields and physical properties are listed i n Table I.
SULFOXAL ANdLOGS DERIVED FROM TETRAH?T)ROTHPAPYRAN
1049
Piepaidion of 4,J-bis (ethy1sul.fmyE) teDmhydrothiap yran-1-diaxide. A mixture of 2.2 g. (0.01 mole) of 4,4-bis(ethylmercapto)tetrahydrothiapyran, 20 mE. of water, and 6.6 g. of concentrated sulfuric acid was placed in a 250-ml. separatory-funnel and heated t o 70". To this mjxture was added in smell portions 5 g. of potassium permanganate in 125 ml. of Ivater heated t o 70". The reaction mixture was maintained a t a teniperature of 65-70' and shaken vigorousiy for 15 minutes. Saturated sodium acid sulfite solution was then added until the mixture was decolorized. The mixture was cooled and extracted twice with chloroform. The chloroform extract was washed well with saturated sodium acid carbonate and dried over magnesium sulfate. After distilling off the solvent the crude residue was taken up in hot acetone, either alcohol or mater mas added, and the solution was allowed t o stand in an ice-chest overnight. The white crystals were filtered and recrystallized in t h e same manner. Yields and properties of t h e sulfones made are listed in Table 11. SUMMARY
The ethylrnercaptols and corresponding sulfones of several 1,4-tetrahydrothiapyrones and 3-ketothiophane have been made for the first time. Though the sulfones are structurally somewhat similar to the sulfonal type of hypnotic they showed no hypnotic activity when tested on rats. LEXINGTON, KENTUCKY
REFERENCES
(I) B A R K ~ B UMPDHIFF, S, AXD NZWAIAE, J . Org. Chem., 16, 232 (1951). (2) REPTZ, FERN-U~DEE, SXIDER, AND TODBQS, J. Am. C h e w floc., 71, 3433 (1949).
